Abstract 6256: Inhibition of class IIa HDACs potentiates MYC inhibitor-driven cytotoxicity by inducing MYC depletion and oxidative stress in non-small cell lung cancer
Authors: Jina Park, Ying-Yu Chen, Jennie Cao, Michelle Vaz, Ray-Whay C. Yen, Stephen B. Baylin, Michael J. Topper
Journal: Cancer Research (2023)

Abstract Lung cancer is the most common cause of cancer mortality worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Dysregulation and/or overexpression of MYC are widely implicated in NSCLC, which suggests that MYC may be a promising therapeutic target for the treatment of NSCLC. Recently, two direct MYC inhibiting agents with improved in vivo efficacy and tolerability, MYCi975 and Omomyc, have been developed. To define new drug strategies that could potentiate the therapeutic effects of MYC inhibitors, transcriptome datasets from MYCi975 and Omomyc studies were reanalyzed. These data revealed the induction of two class IIa histone deacetylases (HDACs), HDAC5 and HDAC9, upon MYC inhibition. Importantly, class IIa HDACs are involved in cancer proliferation, aggressiveness, and prognosis. In addition, novel agents that selectively inhibit class IIa HDACs have demonstrated promising anti-tumor efficacy; thus, suggesting potential therapeutic benefits from dual targeting of MYC and class IIa HDACs. We assessed the treatment efficacy of MYCi plus class IIa HDACi across 18 NSCLC cell lines, 10 of which demonstrated substantial reduction of cell viability upon combination treatment. Querying of driver mutation spectra associated with differential drug response in our cell line panel defined that EGFR mutant cell lines exhibited resistance, while STK11 or Ras mutant cell lines were sensitive to our drug paradigm. Gene set enrichment analysis comparing the transcriptomes of sensitive versus resistant cell lines revealed that MYC Targets, Oxidative Phosphorylation, and Reactive Oxygen Species (ROS) pathways were activated in combination treatment responsive cell lines. RNA sequencing on treated cell lines identified large-scale transcriptional shifts facilitated by combination treatment, including suppression of MYC, cell cycle, and mitochondrial pathways. Furthermore, G1/S arrest and elevated mitochondrial ROS levels in combination drug-treated cells were confirmed using flow cytometry. Concordant with the role of MYC as a key cell cycle regulator, MYC protein levels were decreased in the combination treatment group as compared to the vehicle or mono-treatment groups. Importantly, both MYC overexpression and ROS scavenger treatment partially rescued the reduction of cell viability by combination treatment, suggesting both MYC depletion and ROS elevation as contributors to therapeutic efficacy driven by combination treatment. Expanding these studies to in vivo models, we discern that combination MYC and class IIa HDAC inhibition significantly reduced tumor burden in a patient-derived xenograft model of human NSCLC. In summary, we define here a novel drug paradigm combining MYC and class IIa HDAC inhibitors, which potentiates anti-tumor efficacy in NSCLC via MYC depletion and oxidative stress. Citation Format: Jina Park, Ying-Yu Chen, Jennie Cao, Michelle Vaz, Ray-Whay C. Yen, Stephen B. Baylin, Michael J. Topper. Inhibition of class IIa HDACs potentiates MYC inhibitor-driven cytotoxicity by inducing MYC depletion and oxidative stress in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6256.